Diverging mRNA and Protein Networks in Activated Microglia Reveal SRSF3 Suppresses Translation of Highly Upregulated Innate Immune Transcripts

Boutej, Hejer; Rahimian, Reza; Thammisetty, Sai Sampath; Béland, Louis-Charles; Lalancette–Hébert, Mélanie; Križ, Jasna

doi:10.1016/j.celrep.2017.11.058

Cited by 77 publications

(85 citation statements)

References 49 publications

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“…Interestingly, single‐cell RNAseq has been shown, depending on the analysis depth, to detect only abundant transcripts (Peterson et al , ). Several transcripts and proteins of the DAM did not overlap (Keren‐Shaul et al , ; Mrdjen et al , ), while a marked dissociation of mRNA and protein networks was described in microglia exposed to LPS challenge (Boutej et al , ). It should be noted also, on a positive note, that mass cytometry data could be useful for instructing isolation procedures, through the identification of cell surface markers that can be used (Mrdjen et al , ).…”

Section: Introductionmentioning

confidence: 99%

Microglial subtypes: diversity within the microglial community

et al. 2019

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Microglia are brain‐resident macrophages forming the first active immune barrier in the central nervous system. They fulfill multiple functions across development and adulthood and under disease conditions. Current understanding revolves around microglia acquiring distinct phenotypes upon exposure to extrinsic cues in their environment. However, emerging evidence suggests that microglia display differences in their functions that are not exclusively driven by their milieu, rather by the unique properties these cells possess. This microglial intrinsic heterogeneity has been largely overlooked, favoring the prevailing view that microglia are a single‐cell type endowed with spectacular plasticity, allowing them to acquire multiple phenotypes and thereby fulfill their numerous functions in health and disease. Here, we review the evidence that microglia might form a community of cells in which each member (or “subtype”) displays intrinsic properties and performs unique functions. Distinctive features and functional implications of several microglial subtypes are considered, across contexts of health and disease. Finally, we suggest that microglial subtype categorization shall be based on function and we propose ways for studying them. Hence, we advocate that plasticity (reaction states) and diversity (subtypes) should both be considered when studying the multitasking microglia.

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Section: Introductionmentioning

confidence: 99%

Microglial subtypes: diversity within the microglial community

et al. 2019

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“…However, the impact of cytoplasmic TDP-43 misaccumulation on mRNA translation in vivo has remained unknown. Here we used a Ribotag method (24) in combination with mass spectrometry to study the translational pro les of neurons in one-year old transgenic mice expressing ALS-linked hTDP-43 A315T mutant, a model of ALS/FTD (12). Our study revealed for the rst time that TDP-43 proteinopathy can cause translational deregulation of speci c mRNAs.…”

Section: Discussionmentioning

confidence: 99%

“…TRAP protocol described by Heiman and colleagues with small modi cations was used for the study (23,24). Cortex and hippocampal tissue were extracted from the brain and homogenized (10% w/v) together in tissue lysis buffer.…”

Section: Trap Protocolmentioning

confidence: 99%

Induction of autophagy mitigates TDP-43 pathology and translational repression of neurofilament mRNAs in mouse models of ALS/FTD

Kumar

Phaneuf

Cordeau

et al. 2020

Preprint

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Background: TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). So far, there is no therapy available for these neurodegenerative diseases. In addition, the impact of TDP-43 proteinopathy on neuronal translational profile remains unknown. Methods: Biochemical, immunohistology and assay-based studies were done with cell cultures and transgenic mice models. We also used a Ribotag approach combined with microarray and proteomic analyses to investigate the neuronal translational profiles in mouse model of ALS/FTD. Results: Here, we report that oral administration of a novel analog (IMS-088) of withaferin-A, an antagonist of nuclear factor kappa-B (NF-ĸB) essential modulator (NEMO), induces autophagy and reduced TDP-43 proteinopathy in the brain and spinal cord of transgenic mice expressing human TDP-43 mutants, models of ALS/FTD. Treatment with IMS-088 ameliorated cognitive impairment, reduced gliosis in the brain of ALS/FTD mouse models. With the Ribotrap method, we investigated the impact of TDP-43 proteinopathy and IMS-088 treatment on the translation profile of neurons of one-year old hTDP-43A315T mice. TDP-43 proteinopathy caused translational dysregulation of specific mRNAs including translational suppression of neurofilament mRNAs resulting in 3 to 4-fold decrease in levels type IV neurofilament proteins. Oral administration of IMS-088 rescued the translational defects associated with TDP-43 proteinopathy and restored the synthesis of neurofilament proteins, which are essential for axon integrity and synaptic function. Conclusions: Our study revealed that induction of autophagy reduces TDP-43 pathology and ameliorates the translational defect seen in mice models of ALS/FTD. Based on these results, we suggest IMS-088 and perhaps other inducers of autophagy should be considered as potential therapeutics for neurodegenerative disorders with TDP-43 proteinopathies.

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“…While these processes have been widely studied in other cell-types, it has recently become apparent that astrocytes also must have substantial cytoplasmic posttranscriptional regulation: for example, a set of mRNAs enriched on ribosomes in peripheral astrocyte processes(PAPs) have been defined, consistent with sequence-regulated local translation 5 . Likewise, there are clear examples of posttranscriptional regulation, via expression of specific cytoplasmic RBPs, being an essential aspect of differentiation and maturation of neurons 6 , microglia 7 , and oligodendrocytes 8 . However, aside from elegant work on the Fragile X Mental Retardation Protein(FMRP) 9,10 , post-transcriptional regulators of such processes in astrocytes largely remain unknown.…”

Section: Introductionmentioning

confidence: 99%

CRISPR-TRAPSeq identifies the QKI RNA binding protein as important for astrocytic maturation and control of thalamocortical synapses

Sakers¹,

Liu²,

Llaci³

et al. 2020

Preprint

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Quaking RNA binding protein(QKI) is essential for oligodendrocyte development as myelination requires MBP mRNA regulation and localization by the cytoplasmic isoforms(e.g. QKI-6). QKI-6 is also highly expressed in astrocytes, which were recently demonstrated to have regulated mRNA localization. Here, we show via CLIPseq that QKI-6 binds 3'UTRs of a subset of astrocytic mRNAs, including many enriched in peripheral processes. Binding is enriched near stop codons, which is mediated partially by QKI binding motifs(QBMs) yet spreads to adjacent sequences. We developed CRISPR TRAPseq: a viral approach for mosaic, cell-type specific gene mutation with simultaneous translational profiling. This enabled study of QKI-deleted astrocytes in an otherwise normal brain. Astrocyte-targeted QKI deletion altered translation and maturation, while also increasing synaptic density within the astrocyte's territory. Overall, our data indicate QKI is required for astrocyte maturation and demonstrate an approach for a highly targeted translational assessment of gene knockout in specific cell-types in vivo.

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Diverging mRNA and Protein Networks in Activated Microglia Reveal SRSF3 Suppresses Translation of Highly Upregulated Innate Immune Transcripts

Cited by 77 publications

References 49 publications

Microglial subtypes: diversity within the microglial community

Microglial subtypes: diversity within the microglial community

Induction of autophagy mitigates TDP-43 pathology and translational repression of neurofilament mRNAs in mouse models of ALS/FTD

CRISPR-TRAPSeq identifies the QKI RNA binding protein as important for astrocytic maturation and control of thalamocortical synapses

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